Male-Specific W4P/R Mutation in the Pre-S1 Region of Hepatitis B Virus, Increasing the Risk of Progression of Liver Diseases in Chronic Patients

Abstract

bThe issue of hepatitis B virus (HBV) mutations possibly leading to a gender disparity in the progression of liver diseases has not been explored. We aimed to elucidate the relationships of the novel pre-S1 mutations, W4P/R, with the progression of liver diseases and male predominance in a South Korean chronic cohort by use of a molecular epidemiologic study. We developed a fluorescence resonance energy transfer (FRET)-based real-time PCR (RT-PCR) assay for the detection of the W4P/R mutations and applied it to 292 chronic HBV patients. The pre-S1 mutations from 247 (84.6%) of a total of 292 patients were detected by this assay. W4P/R mutants were found to be significantly related to severe liver diseases (hepatocellular carcinoma [HCC] and liver cirrhosis, 12.4% [19/153] of patients, versus chronic hepatitis and asymptomatic carriage, 1.1% [1/94] of patients) (P < 0.001). All of the W4P/R mutants were found in males only. The novel HBV pre-S1 mutations, W4P/R, may be associated with disease severity in male patients chronically infected with HBV genotype C. The W4P/R mutations may provide in part an explanation for the relatively high ratio of male to female incidence in HCC generation in South Korean chronic HBV patients. Hepatitis B virus (HBV) infection is a global health problem, and Ͼ350 million people are chronic carriers of the virus (1, 2). The infection is associated with a wide spectrum of clinical manifestations, ranging from acute or fulminant hepatitis to various forms of chronic infection, including asymptomatic carriage, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) (3). South Korea is recognized as an area where HBV infection is endemic; based on the Korean National Health and Nutrition Survey of 2007, the prevalence of HBsAg was 4.2% in men and 3.1% in women at that time (4). Moreover, it was reported that the extraordinary prevalence in South Korea of HBV genotype C2, which is known to be more virulent than HBV genotype B (5), might contribute to the distribution of the characteristic HBV mutation patterns related to the progression of liver diseases (6-14).HBV produces three envelope proteins, all of which are encoded in the pre-S/S open reading frame. They have been suggested to play a role in virus assembly (15, 16) and attachment to hepatocytes (17). It has also been proposed that large surface proteins (LHBs) with mutations, particularly deletions, in the Pre-S region might contribute to hepatocarcinogenesis through the induction of an endoplasmic reticulum (ER) stress pathway or trans-activating capacity (18-20). HBV pre-S mutations prevail in countries where HBV infection is highly endemic. In general, the Pre-S2 region is known to be more prone to mutations than the Pre-S1 region. Therefore, so far, the mutation patterns related to the progression of liver disease have been described more frequently in the Pre-S2 than in the Pre-S1 region. Recently, we showed a novel pre-S1 deletion type leading to 11 amino acid deletions from the pre-S1 start codon that is related t...

Molecular analysis of Hepatitis B virus sub‐genotypes and incidence of preS1/preS2 region mutations in HBV‐infected Egyptian patients from Mansoura

“…Finally, it should be mentioned, it was demonstrated previously that the point mutation W4P in the preS1 gene was restricted only in male patients ).…”

Parasite evolution in response to sex‐based host heterogeneity in resistance and tolerance

“…Finally, there is currently a shortage of experimental treatments on these issues, and empirical evidence for sex‐specific evolution of parasites is limited (but see Lee et al ., ). Experimental evolution approaches (see Masri et al ., , on a related topic) may provide opportunities to demonstrate these differences, as they allow to separate evolution of a parasite in one of the sexes or even to control the sex ratio of the host population.…”

“…It would be worthwhile to test these hypotheses in experimental populations, for instance by manipulating intrinsic survival through limiting reproduction, increasing resource availability or otherwise artificially manipulating the intrinsic mortality in one sex. Finally, there is currently a shortage of experimental treatments on these issues, and empirical evidence for sex-specific evolution of parasites is limited (but see Lee et al, 2013). Experimental evolution approaches (see Masri et al, 2013, on a related topic) may provide opportunities to demonstrate these differences, as they allow to separate evolution of a parasite in one of the sexes or even to control the sex ratio of the host population.…”

Induction of endoplasmic reticulum-derived oxidative stress by an occult infection related S surface antigen variant

“…Moreover, an extraordinary prevalence of genotype C2 was reported in this area [3] . This genotype is more virulent than genotype B [4] , and it may contribute to the distribution of characteristic HBV mutation patterns that are related to the progression of liver diseases [5][6][7][8][9][10][11][12][13][14][15] . HBV surface open reading frames (ORFs) encode 3 types of proteins that share C terminals, large (L), middle (M), and small (S) surface antigen.…”